P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

ProductQualityManagement
DeborahBaly,Ph.D
Sr.Director,CommercialProduct
QualityManagement,GNE/ROCHE
1

Presentation Outline:
Product Quality Management Regulatory landscape and
need for integrated product quality management
Role of the Product Quality Steward Product quality
oversight by linking systems, data, and people
Product Lifecycle Management - Commercial Product
Lifecycle approach
Conclusions

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

RegulatoryLandscape
GrowingExpectationsforModernManufacturing
Qualityisbuiltin
LifecycleapproachfromDevelopmenttoProduct
Discontinuation
UnderstandcomplexsupplychainCMOnetworks
Robustprocessmeasurement&analyticaltools
Realtimeassessmentofproduct&processcapability
Maintainingstateofcontrolthroughoutcommerciallifecycle

ProductQualityManagement:
FundamentalElements
Product Complaints
Identifying early warning signals of product quality
issues in the field
Product Assessment & Trending
Proactive assessment of product quality
attributes across the manufacturing process
Product Quality Stewards
Single point of Contact for Quality to key stakeholders
Routine assessment of product control plans to address trends
8 Qtr Plan provides foresight and proactive approach
QC testing network support
Harmonized approach to test method execution & support
Raw Materials & Stability Program Management
Critical Reagent & Reference Material Program Management
Analytical methods management
Scientific rigor engrained in analytical method performance
Product control systems based on science
Seamless product transfers
& assessment of consistency
Slide4

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

ProductQualityManagement
Benefits
Proactively minimize risks to patients, operations, and supply
chain through early detection and endtoend product oversight
MeetsRegulatoryexpectationsofscience andriskbasedproduct
knowledgemanagement
Riskassessmentofproductqualityattributeslinkedto
controlstrategy
Proactivemonitoring&trendingofproductdata
ProductspecificcontrolplansacrosstheglobalMfgnetwork
Afocusoninnovation,lifecyclemanagementandcontinual
improvement
Maintain reputation as a trusted source of high quality product
among patients, regulators, and industry

Presentation Outline:
Product Quality Management Regulatory landscape and
need for integrated product quality management
Role of the Product Quality Steward product quality
oversight by linking systems, data, and people
Product Lifecycle Management - Commercial Product
Lifecycle approach
Conclusions

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

Supply Chain Teams:

Product Quality Steward Role
PMTL
PROP
Finance

Planning
Quality
Steward

PTTL DP

PSCT
PTTL DS

CMC
RegA

Quality
Steward

Launch
STL Dev CMC

Lot
Disposition

STL
External
Quality

Ad Hoc Quality Sub Team Members

Product Quality
Sub-Team

Change Control
Methods Mgmt and Technology
Inspection Mgmt

QC IP/FP

Product
Complaints

Compliance

Investigations

Stability

External QC
Validation

Product Quality Steward Role

Leadership & Accountability
OwnmonthlyproductspecificHealthAssessmentReport&
escalationofriskstoseniormanagement
OwnProductspecificRiskAssessments&accountabletodrive
completionofriskreductionactivities
LeadProductQualitySupplyTeam
QualitySPOConProductSupplyChainTeam;responsiblefor
ensuringthatQualityrequirementsaremet
SPOCforQualityforTechTransferTeams
ReviewAPQRsandARsforaccuracyandcompletenessaswell
asforlifecyclemanagementcommitments

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

Product Quality Steward Role

Key Accountabilities
Knowledge&LifecycleManagement
ManageproductcommercializationwithIMPQuality
ConduitofInformationwithinQualityforProductKnowledge
OwnandmanageE2EControlPlansandQualityLifecycleManagement
(continualimprovement)forproduct

DecisionMaking,Investigations&Issues
ManageteamofQualitySMEsforcrosssiteinvestigations/issues
InfluenceanddrivedecisionsatProductQualitySupplyChainTeams
Escalateproductspecificproductqualityandcomplianceissuesfor
reviewatrelevantQualityReviewBoardsand/orSeniorManagement
Decisionmakerforlifecyclemanagementandproductcontrolplans

QualityRiskManagement
UnderstandingE2ESupplyChain
Scope: End-to-end supply chain for commercial
products

Initiate Quality
Risk Management Process

Data collection checklist: complaints, investigations,

stability, QC, lot disposition, audits, supplier quality,
APQR, validation, facilities, warehousing, distribution,
PQST input, etc.
Score each risk for severity, occurrence & detectability
(S, O and D):
Up to DP: Quality/Regulatory scoring matrix
For distribution and on: Patient Safety scoring matrix

Cross-product review to identify additional risks

Not acceptable/intolerable risks need risk reduction
actions identified
When risk reduction activities are completed, a rationale
for acceptance of residual risk is documented
CAPAs initiated and tracked within Quality System

Risk Identification
Risk Analysis

Risk Communication

Gather data & reconfirm risk is still relevant

Risk Assessment

Risk Evaluation

Risk Control

Risk Reduction
Risk Acceptance

Output/Result of the Quality

Risk Management Process
Risk Review

Review Events

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

Presentation Outline:
Product Quality Management Regulatory landscape and
need for integrated product quality management
Role of the Product Quality Steward Product quality
oversight by linking systems, data, and people
Product Lifecycle Management - Commercial Product
Lifecycle approach
Conclusions

ICH Q10 Elements

Product Quality Assessment
ICH Q10 Pharmaceutical Quality System, Process
Performance and Product Quality Monitoring System 3.2.1:
Pharmaceuticalcompaniesshouldplanandexecuteasystem
forthemonitoringofprocessperformanceandproduct
qualitytoensureastateofcontrolismaintained.
Usequalityriskmanagementtoestablishthecontrol
strategy.
Providethetools(e.g.,datamanagementandstatistical
tools)formeasurementandanalysisofparametersand
attributesidentifiedinthecontrolstrategy
Identifysourcesofvariationaffectingprocessperformance
andproductqualityforpotentialcontinualimprovement
activities
Knowledgemanagement

By Deborah Baly, PhD

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

Post-Approval Lifecycle Management

Plan (PALM).Leveraging QbD
Post-Approval
Lifecycle
Management
Plan

Assessment &
Management of
Process Changes

Management of
Analytical
Control System
Changes

Process
Monitoring:
Process & Quality
Attributes

Health Authority expectation that commercial products are monitored and

continuously improved post-approval
License claims are expected to be updated as sponsor learns more about the
product and process

Management of Analytical Control

System Changes
Leveraging PALM Approach for Control System Re-Assessment
AssaySpecificTriggers

ControlSystemTriggers

Recommendationinresponseto
outoftrendresults
Recommendationasaresultof
AnnualProductReview(APR/PQR)
process
Implementationofbetterassay
forothercommercialproducts

Recommendationinresponseto
outoftrendresults

Assesssuitabilityofassay

Newknowledgefromadditional
clinical/nonclinicalstudiesforthis
product

Determineifoptionsexistto
improvecurrentassayperformance
Determinesuitabilityofnewassays

Recommendationasaresultof
AnnualProductReview(APR/PQR)
process
Asignificantprocesschangeornew
devicebeingimplemented

Mandatedevery5yearsifnoother
triggersrequireassessment

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

Product & Process Monitoring

NOT
CAPABLE

CAPABLE

GoalofProductMonitoring:EnsuringaContinuedStateofControlofProcess
PerformanceandProductQualityDelivered!

STABLE

NOT STABLE

The Place to be!!

You cant tell what the quality of

the next unit will be.

Target not around the center of

specification ranges & variation is
too large

Not acceptable!

ProcessCapableChart:
Capablevs.UncapableProcess
ProcessCapability:isastatisticalestimateoftheoutcomeofacharacteristic
fromaprocessthathasbeendemonstratedtobeinastateofstatisticalcontrol.
ProcessCapabilityIndex:astatisticalmeasureofprocesscapability
CpK=RatioofSpecRangetoTotalDataVariation
CpM=Measurementofhowcenteredaroundthetargettheprocesscandeliver

Acapableprocessthatdeliversontarget
forthisCQA:
CpK>1
Processdeliversrightontarget.

Correlation of CpK value with % Defective Product

Notacapableprocess,eventhoughit
centersaroundthetarget
CpK<1
Cpk

% Defective product

0.8

0.819

1.0

0.135

1.33

0.0033

1.8

0.00033

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

Example1: A Un-Capable Process for

Potency Assay (Cpk <1.0, and not centered)
Analyticalmethodandspecificationnotoptimized
ExcessiveOOSsandOOTsobserved
P r o d u c t_ A T e s t M e tho d _ 1 2 5 B e f o r e M e tho d / S p e c C ha ng e
Individual Value

I C ha r t

C a p a b ility H isto g r a m

7.0

U C L = 7.033

6.5

_
X = 6.346

L SL

U SL

S p e cifica tio n s
LS L
5.47
U S L 6.86

6.0
L C L = 5.658
1

10

13

16

19

22

25

28

31

5.6

5.8

6.0

Moving Range

M o v ing R a ng e C ha r t
0.8

U C L = 0.8448

0.4

__
M R = 0.2586

6.4

6.6

6.8

A D : 0 .397 , P : 0.3 50

LC L= 0

0.0
1

10

13

16

19

22

25

28

31

5.5

6.0

6.5

W ith in

W ith in
S tD e v 0 . 2 2 9 2 2 5
Cp
1.01
C pk
0.75

6.50
6.25

15

20
O b s e rv a tio n

25

O v e ra ll
S tD e v 0 . 2 2 0 1 9 2
Pp
1.0 5
P pk
0.7 8
C pm
*

O v e ra ll

6.00
10

7.0

C a p a b ility P lo t

L a st 2 5 O b s e r v a tio ns

Values

6.2

No r m a l P r o b P lo t

S p e cs

30

Example1continued:
Reconfigured Capable Process
Bothanalyticalmethodandspecificationhavebeenoptimizedinorderto
achieveacapable(CpK=1.29)andcenteredprocessforthepotencyassay.
Pr oduc t _A Te s t Me t hod_125 A ft e r Me t hod/ Spe c Cha nge
I C har t

C apability H istogr a m

Individual Value

6.5

UC L= 6.413

LSL

U SL

S pe cifica tio ns
LS L
5.16
U S L 6.55

_
X = 5.933

6.0

5.5

LC L= 5.453
1

10

13

16

19

22

25

5.2

5.4

5.6

M ov ing Range C har t

Moving Range

6.0

6.2

6.4

Nor ma l P r ob P lot
A D : 0.417, P : 0 .308

UC L= 0.5896
0.50

__
MR = 0.1805

0.25

0.00

LC L= 0

10

13

16

19

22

25

5.50

6.4

W ithin
S tD e v 0.159979
Cp
1.45
C pk
1.29

6.0
5.6
5

10

15
Obse rv a tio n

20

5.75

6.00

6.25

C a pability P lot

L a st 2 5 O bser v ations

Values

5.8

25

W ithin
O v e ra ll
S pe cs

O
S tD e v
Pp
P pk
C pm

v e ra ll
0.159204
1.46
1.29
*

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

QC Method Monitoring
Program
Integraltotheanalyticalmethodlifecyclemanagement
Focusisonpurityandpotencymethods
Ensuresmethodperformanceacrosscomplex
manufacturingnetwork&testingsitesisconsistent
Analysisofreferencematerial,assay&productcontrolsdata

Providesanalyticaltrendingsupporttoprocess/product
trending
AkeycomponentoftheAnnualProductReview(APR
RegulatoryrequirementbyHealthCanada

Stabilityinvestigationsupport
Servesasaninspectiontoolforanalyticalmethods

Example:
QCMethodMonitoringResults

Top: Reference Material data trend

chart for all valid assays across 6
global testing sites
Bottom: Site Mean trend chart for
the 6 sites showing that the method
performance is consistent throughout
all sites

Method Monitoring limits

System suitability limits

A Mab product, Ion Exchange Method

P8: Pharmaceutical Quality System Elements:

Process Performance and Product Quality Monitoring System

By Deborah Baly, PhD

PALM&AnnualProductReview

Excursion data monitored via Discrepancy

System per Quality System Requirement

Performed and documented by MSAT

Documented by QA per QS
Requirement

Documented by QC
per QS requirement

Performed & Documented by

Performed
and Documented by QA per QSR
QA
per QS Requirement

Product Quality Monitoring Information would be documented with APR

Conclusion

ProductQualityManagement:
Theendtoendqualityreviewandcontrolof
Rochesproductsthroughoutthesupplychain
Drivescontinualimprovementthroughoutthe
productandprocesslifecycletoensureareliable
supplyofqualityproductstoourpatients

Raw Materials Drug Substance Drug Product

EndtoEnd

Testing

Distribution
22